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Modeling the response of troponin C to calcium in increasingly complex systems

Siddiqui, Jalal K
http://rave.ohiolink.edu/etdc/view?acc_num=osu1480258715871156

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Biophysics.
Troponin C (TnC) is a calcium-sensing switch that regulates contraction and relaxation in skeletal and cardiac muscle. Mutations in troponin (TnC, troponin I (TnI), troponin T (TnT)) that alter the apparent Ca2+ binding properties of TnC have been implicated in several cases of cardiomyopathy. Further studies have focused on TnC as a target for pharmacological intervention, and a recently engineered Ca2+-sensitized TnC variant has been shown to enhance contractility in mice with myocardial infarction. Previous studies have shown that the Ca2+ binding properties of TnC depend not only on troponin interactions but also upon interactions of many other myofilament proteins. Furthermore, many of these proteins are targets for phosphorylation and other post-translational modifications that alter the apparent Ca2+ binding properties of TnC. In this regard, TnC is not merely a simple switch, but a central hub receiving input from several other proteins. Studies have shown that while isolated TnC has a low Ca2+ binding affinity, the Tn complex has a high Ca2+ binding affinity. Thin filaments containing the Tn complex and actin/tropomyosin have an intermediate affinity which is restored to high affinity similar to that of the Tn complex by the addition of S1 myosin. One of the major questions we sought to answer was what could account for the differences in Ca2+ affinity between these different states of TnC. Furthermore, studies demonstrated that several TnI and TnT modifications altered the Ca2+ properties of thin filaments but did not change the Tn complex properties. Based on previous studies, we know that TnC-TnI interactions play a prominent role in modulating TnC’s Ca2+ sensitivity via stabilization of TnC’s Ca2+ binding. We hypothesize that since TnC and TnI are proximally confined on the Tn complex, they are able sense one another more than if they were separated in solution (i.e. they experience a high effective concentration of each other). With regards to thin filaments, actin/tropomyosin compete with TnC for TnI, lowering this effective TnI concentration and hence lowering the apparent Ca2+ sensitivity of TnC. Studies with TnC in the presence of TnI peptides demonstrated that TnC’s Ca2+ affinity and dissociation kinetics were regulated by TnI concentration in a dose dependent manner. Furthermore, as TnI peptide concentration was increased, TnC’s Ca2+ affinity and dissociation kinetics plateaued toward the Ca2+ affinity and dissociation kinetics of TnC-TnI chimeric proteins in which the regulatory regions of TnC and TnI were tethered together. While the chimera had a 1:1 TnI:TnC ratio, the Ca2+ binding properties were similar to that of TnC in the presence of an order of magnitude more TnI peptides. Based on the results of these studies as well as previous studies in our laboratory, we developed a new mathematical model that described how TnC-TnI interactions regulated Ca2+ binding on TnC. We demonstrated that at high effective TnI concentration, we were able to model Tn Ca2+ binding properties. Lowering the effective TnI concentration allowed us to model thin filament Ca2+ binding properties. Furthermore, we have used this model to predict mechanisms of several TnI/TnT modifications that have altered the Ca2+ binding properties in thin filaments and in some cases Tn complexes. Several of these modifications can be modeled by simply adjusting the thin filament effective TnI concentration.
Jonathan Davis, PhD (Advisor)
Brandon Biesiadecki, PhD (Committee Member)
Mark Ziolo, PhD (Committee Member)
Thomas Hund, PhD (Committee Member)
211 p.
Biophysics; Physiology
Cardiac Troponin C Troponin I Muscle Regulation Contraction Relaxation

Recommended Citations

Citations

  • Siddiqui, J. K. (2016). Modeling the response of troponin C to calcium in increasingly complex systems [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1480258715871156

    APA Style (7th edition)

  • Siddiqui, Jalal. Modeling the response of troponin C to calcium in increasingly complex systems. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1480258715871156.

    MLA Style (8th edition)

  • Siddiqui, Jalal. "Modeling the response of troponin C to calcium in increasingly complex systems." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1480258715871156

    Chicago Manual of Style (17th edition)

osu1480258715871156
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